Heart disease is a major health problem throughout the world. Myocardial infarctions are a significant source of mortality among those individuals with heart disease.
Acute coronary syndrome (“ACS”) denotes patients who have or are at high risk of developing an acute myocardial infarction (MI). This complex includes unstable angina (UA), non-Q-wave cardiac necrosis (NQCN) and Q-wave MI (QMI). Thompson et al., M.J.A. 171; 153 (1999). Typically, ACS is diagnosed when a patient has acute (i.e., sudden onset) chest pain of a cardiac origin that is either new or clearly different from pre-existing, chronic, stable angina; that is, ACS chest pain is more severe, more frequent, occurs at rest, or is longer than 15 minutes in duration. After ACS has been diagnosed, the patient is stratified into UA, NQCN, and QMI, using criteria that are described elsewhere in this application. UA, NQCN, and QMI are believed to represent different stages of plaque rupture and thrombosis. Zaacks et al., J. Am. College Cardiol. 33; 107 (1999). With UA, there typically is no myocardial necrosis. Id. UA, NQCN, and QMI all are characterized by varying degrees of ischemia. Id. Additionally, Q-wave MI generally is understood to result from total occlusion of a coronary artery, whereas UA is caused by a subtotal occlusion. Thompson et al. M.J.A. 171; 153 (1999).
During normal, aerobic metabolism, cardiac tissue uses free fatty acids (FFA) to generate energy. During ischemia induced by UA, NQCN, or Q-wave MI, the heart switches to anaerobic metabolism, using glucose as its primary energy source.
Many other detrimental metabolic changes occur during ischemia in cardiac tissue, including accumulation of excess unoxidized FFA products, inhibition of Ca2+and Na+/K+pumps, and increased levels of cAMP. Additionally, there is decreased secretion of insulin by pancreatic β-cells and excess secretion of glucagon by pancreatic α-cells.
Excess glucagon can lead to myocardial tissue damage; glucagon is also an insulin antagonist and mediates lipolysis in adipose tissue, with release of FFAs. Excess FFAs can lead to free radical formation and consequent tissue damage. Glucagon is one of the so-called counter-regulatory hormones, a group that includes cortisol, growth hormone, and catecholamines, which are released during “stress” conditions, such as ACS, UA, NQCN, fasting, starvation, infection, disease, internal injury, and trauma. The role of such hormones is to counter-regulate the effects of insulin, thereby raising blood glucose and fatty acid levels and producing a generally insulin-antagonistic state. Glucose is a mediator of stress responses and a component of systemic inflammatory reactions.
A variety of therapeutic agents is known for treating Q-wave MI. These include thrombolytic therapy and angiotensin-converting enzyme (ACE) inhibitors. Thompson et al., M.J.A. 171; 153 (1999). PCT Application WO 98/08531 relates to treatment with GLP-1 of a patient suffering from Q-wave MI who is also incapable of auto-regulation of blood glucose.
Agents known for treatment of a subtotal coronary occlusion, which results in UA, include heparin, low-molecular-weight heparin, and nitroglycerine. Thompson et al., M.J.A. 171; 153 (1999). β-blockers can be used to combat myocardial ischemia and left ventricular dysfunction that result from acute MI and UA. Id. Prior to the formation of a fibrin thrombus, which leads to partial or total coronary artery occlusion, it is known that that there is plaque erosion or fissure, followed by platelet aggregation. This aggregation can be treated with aspirin, glycoprotein IIb/IIIa antagonists or clopidogrel. Thompson et al., M.J.A. 171; 153 (1999).
Most therapies for the treatment of UA work by (1) stabilizing or reducing the occlusion, such as the anti-thrombin agents heparin and low-molecular-weight heparin, and the anti-platelet agents aspirin, glycoprotein IIb/IIIa antagonists, or clopidogrel, (2) reducing preload, such as nitroglycerine, (3) reducing afterload, such as ACE inhibitors, or (4) reducing myocardial oxygen demand, such as β-blockers. These therapies do not treat directly the disturbed energy metabolism that results from ischemia and that induces tissue damage. Also, dosages of drugs such as heparin must be controlled carefully to avoid toxic effects of overdose.
As a result, there is a need for therapeutic treatments that can be used preferably beginning at the earliest stages of ACS, and during UA or NQCN, and that will prevent and/or reduce the damage resulting from ACS, including any subsequent Q-wave MI.